Overweight, obesity, and sedentary lifestyles are associated with an increased risk for several cancers in women, including colon, endometrium, postmenopausal breast, kidney, and lower esophageal cancer. Evidence suggests that some of the diabetogenic and adverse cardiovascular consequences of obesity and a sedentary lifestyle are also involved in the etiology of several cancers. Oxidative stress, inflammation, and eicosanoids, which are involved in several phases of carcinogenesis and tumor progression, have been associated with risk or progression of cancers in laboratory and epidemiologic studies. They have also been associated with overweight/obesity or a sedentary lifestyle. The effects of weight loss or exercise in overweight/obese women on these biomarkers are not established, however. The Metabolic Syndrome, a set of risk factors for various chronic diseases, is related to obesity, and it, or its components, are associated with increased cancer risk. We propose to investigate the effects of a completed 12-month randomized controlled clinical trial that tested 3 interventions leading to weight loss and/or increased physical activity: 1) reduced calorie dietary weight loss (mean 9% weight loss, N=118); 2) moderate intensity aerobic exercise (225 min/wk, mean 3% weight loss, N=117); 3) both interventions (mean 11% weight loss, N=116); vs. 4) control (no weight change, N=87) in postmenopausal overweight/obese women aged 50-75 years. The primary aims of the proposed study are to test, compared to controls, the effects of interventions on: 1) oxidative stress (plasma F2-isoprostane, fluorescent oxidation products, oxidized LDL); 2) plasma inflammation markers (TNF1, TNF1- receptor 2) and the anti-inflammation marker IL-10; and 3) prevalence of the Metabolic Syndrome. The secondary specific aims are to examine the extent to which other factors modify the associations between dietary weight loss or exercise with the proposed biomarkers: a) overweight/obesity and body fat mass at baseline; and b) body composition (weight, % body fat) changes during the course of the interventions. An exploratory aim will test intervention effects in a subset of 206 women, on urine prostaglandin PGE2 metabolite (PGE-M) and leukotriene LTE4. The results of this novel study will elucidate potential mechanisms linking energy balance to cancer in women, which will aid in the development of interventions for reducing risk for several cancers. PUBLIC HEALTH RELEVANCE: This project will investigate the effects of reduced-calorie weight loss, exercise, and the combination of these two interventions, on several factors related to cancer risk including oxidative stress and inflammation. The project includes 438 postmenopausal, overweight/obese, sedentary women who have already completed the trial from which blood and urine samples will be used.